Genetic dissection of hypertension (HTN) and co-morbidities, carried out largely through traditional linkage analysis, has mostly been unsuccessful to date in identifying specific genetic variants. Motivated by existing evidence that some of the genetic effects are modulated by age and obesity, the investigators have developed appropriate new methods for gene discovery. This revised application addresses the hypothesis that gene-age and gene-obesity interactions are important in the genotype-phenotype correlations. The growing obesity epidemic world-wide makes it particularly important to investigate whether and to what extent obesity modulates genetic effects on HTN and blood pressure. The primary goal of the proposed developmental research is to understand how genes interact with age and obesity in producing blood pressure and HTN. The research will be carried out using the phenotypic and genotypic data previously collected in the large Family Blood Pressure Program (FBPP) that includes African American, White and Hispanic hypertensive families from 3 Networks, incorporating 11,040 individuals. Our proposed study is highly cost effective because it takes full advantage of these extraordinary resources which exist already. The proposed research will investigate the role of age variation in genetic effects and how obesity modulates genetic effects in HTN and blood pressure by performing linkage analysis using our recent method which has been shown to be very powerful. This study is unique in that ethnic differences in the modulation effects also can be investigated. The current exploratory grant is based on novel modeling concepts and one of the largest samples ever collected on HTN. Identifying appropriate ethnic-specific ages (and the critical obesity levels) when genetic variants exert the most influence opens up new avenues of research in terms of finding specific genetic variants and the optimal timing of interventions as well as the development of new pharmaceutical treatments targeted toward the idiosyncrasies of age, obesity and ethnicity. From a public health perspective, individuals with a modifiable genetic risk of HTN could be identified prior to disease development, and effective and appropriate lifestyle modifications and/or pharmaceutical treatments could be implemented for primary prevention. PUBLIC HEALTH RELEVANCE: Risk for hypertension is not constant across age or obesity levels or between ethnic groups;it is reasonable to assume that genetic effects also are not static. Our novel linkage approach incorporating ethnic-specific gene- age and obesity-age interactions as modulators in hypertensive siblings has the potential to identify individuals with modifiable genetic risk, determine optimal timing of intervention and develop targeted drug treatments.